The present invention relates to a pharmaceutical composition in an aqueous solution form useful for administration to an eye of a subject for treatment or prevention of infectious disease therein. In particular, the present invention relates to such a composition having as an active agent an oxazolidinone antibiotic drug. The field of the present invention also includes therapeutic or prophylactic use of such a composition, and use of such a composition in preparation of a medicament.
Numerous oxazolidinone compounds have been reported as having therapeutically and/or prophylactically useful antibiotic or antimicrobial, in particular an antibacterial, effect. Among such compounds are those illustratively disclosed in the following patents, each of which is individually incorporated herein by reference.
U.S. Pat. No. 5,164,510 to Brickner.
U.S. Pat. No. 5,231,188 to Brickner.
U.S. Pat. No. 5,565,571 to Barbachyn and Brickner.
U.S. Pat. No. 5,627,181 to Riedl et al.
U.S. Pat. No. 5,652,238 to Barbachyn et al.
U.S. Pat. No. 5,688,792 to Barbachyn et al.
U.S. Pat. No. 5,698,574 to Riedl et al.
U.S. Pat. No. 6,069,145 to Betts.
Compounds disclosed in above-cited U.S. Pat. No. 5,688,792 include for example the compound (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, referred to herein as xe2x80x9clinezolid.xe2x80x9d Linezolid has the structure shown in formula (I): 
and is in commercial use as a medicament under the trademark Zyvox(copyright) of Pharmacia Corporation. Linezolid exhibits strong antibacterial activity against gram-positive organisms including those of the following genera: Staphylococcus (e.g., Staphylococcus aureus, Staphylococcus epidermidis), Streptococcus (e.g., Streptococcus viridans, Streptococcus pneumoniae), Enterococcus (e.g., Enterococcus fecalis, Enterococcus faecium), Bacillus, Corynebacterium, Chlamydia and Neisseria.
Many such gram-positive organisms have developed significant levels of resistance to other antibiotics. Oxazolidinone antibiotics are also generally effective against anaerobic organisms such as those of the genera Bacteroides and Clostridia, and against acid-fast organisms such as those of the genus Mycobacterium.
Above-cited U.S. Pat. No. 5,688,792 discloses that antibiotic oxazolidinone compounds, including linezolid, can be formulated as a gel or cream for topical application to skin.
Many oxazolidinone compounds useful as antibiotics do not form, or do not readily form, salts. For these compounds, and where for any reason it is preferred not to provide the antibiotic in salt form, it is generally difficult to formulate the antibiotic as a solution in a pharmaceutically acceptable liquid carrier, particularly an aqueous carrier. Most such compounds have relatively low solubility in water. In the case of linezolid, for example, the solubility at ambient temperature is less than 3 mg/ml and the practical limit of concentration in aqueous solution is about 2 mg/ml.
Where ophthalmic administration of an oxazolidinone antibiotic drug is contemplated, it is desired to achieve sufficiently high concentrations of the drug to be therapeutically effective in treating eye infections while ensuring all or substantially all of the drug is in solution. Undissolved, particulate, forms of any ingredient of an ophthalmic solution can cause irritation upon administration to the eye of a subject. Some have approached the problem of a need to administer drugs with low solubility to an eye by providing sufficiently dilute aqueous ophthalmic solutions of a poorly soluble drug to ensure that the drug is in solution. Such dilute solutions of drug must be administered to an eye more frequently than would a higher concentration solution of the same drug, were it possible to make such a solution.
Use of dilute solutions of oxazolidinones is disclosed in U.S. Pat. No. 6,337,329 B1 (International counterpart published as WO 00/03710), incorporated herein by reference. The patent, specifically, discloses a method of treating bacterial keratitis or bacterial conjunctivitis in an eye, comprising topical administration of an oxazolidinone antibiotic to the infected eye. Preferred oxazolidinone compounds for use according to the method of WO 00/03710 include (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (linezolid) and (S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (eperezolid). The oxazolidinone compound is said to be administered in a formulation such as a solution, cream, ointment, emulsion, suspension or slow release formulation, a solution being preferred. Ophthalmic formulations exemplified therein include 10% and 12% weight/volume solutions of linezolid. At such low concentrations of linezolid, it is further disclosed in U.S. Pat. No. 6,337,329 B1 that the oxazolidinone compound can be used individually, in combination with another oxazolidinone compound, in combination with other antibacterial agents, or in combination with non-antibacterial agents.
International Patent Publication No. WO 00/18387, incorporated herein by reference, discloses additional dilute aqueous ophthalmic compositions comprising an oxazolidinone antimicrobial agent. Preferred oxazolidinone compounds according to WO 00/18387 are those of above-cited U.S. Pat. No. 5,627,181. The oxazolidinone component of the compositions was disclosed to typically be present in a concentration of from about 0.1 to about 1.0 percent by weight of the composition (p. 8). The international patent publication also disclosed that the compositions can further comprise an anti-inflammatory agent.
Where ophthalmic administration of an oxazolidinone antibiotic drug is contemplated, it is desired to be able to administer a pharmaceutically effective dose in as small a volume as possible, without having anything in the ophthalmic solution likely to irritate the eye. It will readily be understood that it is difficult to achieve such concentrations by administration of a relatively small volume of a composition wherein the drug is present in dissolved form, unless the composition has a relatively high drug loading, and in particular a drug loading substantially above the limit of solubility in water of most oxazolidinone antibiotics not in the form of a salt.
Derivatives of cyclodextrin, including xcex1-, xcex2, and xcex3-cyclodextrins and derivatives thereof, such as ether and mixed ether derivatives, and derivatives bearing sugar residues have been disclosed as being suitable for use in the solubilization of various drugs that are only sparingly soluble in water. EP 0149 197 B2 (Canadian counterpart, CA 1222697) discloses the suitability of partially etherified xcex2-cyclodextrin and derivatives thereof, including hydroxyethyl, hydroxypropyl, and hydroxypropyl-methyl-xcex2 cyclodextrin for the solubilization of various types of drugs which are instable or only sparingly soluble in water. None of the drugs disclosed by EP 0149 197 B2 as having been solubilized with one or more of the partially etherified xcex2-cyclodextrins was an antibiotic, much less an oxazolidinone. Likewise, U.S. Pat. No. 4,727,064 discloses the use of hydroxypropyl-xcex2-cyclodextrin and the use of mixtures of that cyclodextrin derivative, diethylaminoethyl-xcex2-cyclodextrin, carboxymethyl-xcex2-cyclodextrin, and carboxamidomethyl-xcex2-cyclodextrin to assist in the dissolution of drugs, but does not disclose the solibilization of any oxazolidinone using such a solubility enhancer. Various sulfoalkyl ether cyclodextrin derivatives, including sulfobulylether-xcex2-cyclodextrin, and their utility in solubilizing certain active agents are disclosed in U.S. Pat. Nos. 5,134,127; 5,376,645. Uses of such sulfoalkyl ether cyclodextrin derivatives in solubilizing additional active agents are disclosed in U.S. Pat. Nos. 5,134,127, 5,874,418; 6,046,177; and 6,133,248.
Multi-dose formulations, including ophthalmic formulations, typically contain preservatives in order to maintain sterility after opening and during use. U.S. Pat. No. 5,985,310 notes problems with cyclodextrins inactivating the antimicrobial activity of quaternary ammonium compounds and other preservatives pharmaceutical compositions containing cyclodextrins. That patent discloses the use of certain preservatives, including benzalkonium halide compounds, polymeric quaternary ammonium compounds, and quaternary ammonium alkylene glycol phospholipid derivatives that do not interact with cyclodextrins in a way that significantly reduces or eliminates their antimicrobial preservative activity in a solution containing cyclodextrins.
WO 97/10805 notes a similar negative impact of cyclodextrins on quaternary ammonium salt preservatives in aqueous ophthalmic solutions. WO 97/10805 discloses a means of eliminating this negative impact on such preservatives by including an alkylene glycol in aqueous ophthalmic solutions containing cyclodextrin or a cyclodextrin derivative, and a quaternary ammonium salt preservative. Many different drugs are listed as being suitable for use in such formulations, however, none are oxazolidinones.
The references above indicate that cyclodextrins and derivatives thereof can be suitable for solubilization of a variety of different drugs with low solubility. The references summarized above also indicate that when preservatives are included in solutions containing cyclodextrins, at least some preservatives interact with the cyclodextrins in such a way as to inhibit the effectiveness of the preservatives. Even preservatives or preservative systems that do not react with the cyclodextrin component of a formulation could react with an eye upon administration, or with other components of the formulation. None of the references described above disclose any formulation of an oxazolidinone antibiotic drug and a cyclodextrin compound, much less such an oxazolidinone formulation suitable for ophthalmic delivery.
A need, therefore, exists for a solution composition of an oxazolidinone antibiotic drug having a drug loading substantially in excess of the practical limit of solubility of the drug in water. A particular need exists for an ophthalmically deliverable solution composition of an oxazolidinone antibiotic drug having a relatively high concentration of the drug and a solubilization agent, such as a cyclodextrin or derivative thereof, but without any preservative likely to react with an eye upon administration thereto or with other components of the composition.
These and other needs will be seen to be met by the invention now described.
The present invention provides a preservative free pharmaceutical composition suitable for topical administration to an eye, the composition comprising: (a) an oxazolidinone antibiotic drug in a concentration effective for treatment or prophylaxis of a gram-positive bacterial infection of at least one tissue of the eye, the concentration being above the practical limit of solubility of the drug in an aqueous solution at a physiologically compatible pH; and (b) a pharmaceutically acceptable cyclodextrin compound at a cyclodextrin concentration sufficient to maintain the drug in solution at the drug concentration.
It is believed, without being bound by theory, that the enhanced solubility of the oxazolidinone drug in a composition of the invention is due to association of at least a portion of the drug with the cyclodextrin. It is further believed that at least one mechanism by which the drug associates with the cyclodextrin compound to enhance solubility of the drug in an aqueous medium is through formation of an inclusion complex. Such complexes or conjugates are known in the art to form with a variety of drugs, and a number of advantages have been postulated for use of cyclodextrin-drug complexes in pharmacy. See for example review articles by Bekers et al. (1991) in Drug Development and Industrial Pharmacy 17: 1503-1549; Szejtli (1994) in Medical Research Reviews 14: 353-386; and Zhang and Rees (1999) in Expert Opinion on Therapeutic Patents 9: 1697-1717.
It is also believed, without being limited by theory, that the interaction between the cyclodextrin compound and the oxazolidinone antimicrobial drug in the compounds of the invention is further enabled by the lack of preservatives in solution that can interact with the cyclodextrin compound and inhibit its solubilization of the antimicrobial drug.
Formulations of various drugs with various cyclodextrins have been proposed in the patent literature, including the patents and publications referenced below.
U.S. Pat. No. 5,670,530 to Chen and Shishido discloses compositions comprising a rhodacyanine anti-cancer agent and a cyclodextrin.
U.S. Pat. No. 5,756,546 to Pirotte et al. discloses compositions comprising nimesulide and a cyclodextrin.
U.S. Pat. No. 5,807,895 to Stratton et al. discloses compositions comprising a prostaglandin and a cyclodextrin.
U.S. Pat. No. 5,824,668 to Rubinfeld et al. discloses compositions comprising a 5xcex2 steroid drug and a cyclodextrin.
International Patent Publication No. WO 96/32135 discloses compositions comprising propofol and a cyclodextrin.
International Patent Publication No. WO 96/38175 discloses compositions comprising an antiulcerative benzimidazole compound and a branched cyclodextrin-carboxylic acid.
International Patent Publication No. WO 97/39770 discloses compositions comprising a thrombin inhibitor and a cyclodextrin.
International Patent Publication No. WO 98/37884 discloses compositions comprising a 3,4-diarylchroman compound and a cyclodextrin.
International Patent Publication No. WO 98/55148 discloses compositions comprising a sparingly water-soluble drug, a cyclodextrin, a water-soluble acid and a water-soluble organic polymer.
International Patent Publication No. WO 98/58677 discloses compositions comprising voriconazole and a cyclodextrin.
International Patent Publication No. WO 99/24073 discloses compositions comprising a taxoid such as paclitaxel or docetaxel and a cyclodextrin.
International Patent Publication No. WO 99/27932 discloses compositions comprising an antifungal compound of defined formula and a cyclodextrin.
However, the degree of enhancement of solubility achievable through complexation with cyclodextrins of a particular drug or class of drugs is not generally predictable. Cyclodextrins are expensive excipients and in many cases the degree of enhancement of solubility, or other benefit obtained, has not economically justified the increased cost of a formulation arising from addition of a cyclodextrin. The present invention is based in part on the discovery that addition of a relatively modest 4 amount of a cyclodextrin compound, in a preservative free solution, increases the solubility of an oxazolidinone antibiotic drug to a surprising degree. This enhancement in solubility, among other benefits, makes it possible for the first time to ophthalmically deliver a therapeutically or prophylactically effective dose of the oxazolidinone in a minimal number of doses.
As used herein, term xe2x80x9cpreservative freexe2x80x9d refers to the fact that no detectable amount of preservative is found to be present in a solution, such as the composition of the present invention.
The term xe2x80x9cpharmaceutically acceptablexe2x80x9d in relation to a cyclodextrin or other excipient herein means having no persistent detrimental effect on the eye or general health of the subject being treated. The pharmaceutical acceptability of a cyclodextrin depends, among other factors, on the particular cyclodextrin compound in question, on its concentration in the administered composition, and on the route of administration. For example, use of xcex2-cyclodextrin as an excipient in intravenous compositions is limited by hemolytic and nephrotoxic effects, but is generally non-toxic when administered orally.
The term xe2x80x9cpractical limit of solubilityxe2x80x9d in relation to a drug means the highest concentration at which the drug can be formulated in solution without risk of precipitation or crystallization of the drug during the normal range of manufacturing, packaging, storage, handling and use conditions. Typically, the practical limit of solubility is considerably lower than the true solubility limit in a given aqueous medium, for example about 70% of the true solubility limit. Thus, illustratively, for a drug having a true solubility limit in a given aqueous medium of 2.9 mg/ml, the practical limit of solubility is likely to be about 2 mg/ml.
Except where the context demands otherwise, use of the singular herein will be understood to embrace the plural. For example, by indicating above that a composition of the invention comprises xe2x80x9can oxazolidinone antibiotic drugxe2x80x9d and xe2x80x9ca pharmaceutically acceptable cyclodextrin compoundxe2x80x9d, it will be understood that the composition can contain one or more such drugs and one or more such cyclodextrin compounds.
In one embodiment, present invention provides a method of treating an existing bacterial infection in the eye of a subject, comprising ophthalmically administering a therapeutically effective dose of the preservative free pharmaceutical composition, as described above. Infective diseases of the eye for which compositions and methods of the invention are useful include without limitation conjunctivitis, keratitis, blepharitis, blepharoconjunctivitis, orbital and preseptal cellulitis and endophthalmitis. In preferred methods the infected tissue is one that is directly bathed by the lacrimal fluid, as in conjunctivitis, keratitis, blepharitis and blepharoconjunctivitis.
In infective diseases of the eye where the causal organism is non-bacterial, there can be benefit in prophylactic use of a composition of the invention to control secondary bacterial infections. Examples of such situations include conjunctivitis and keratitis of viral etiology, e.g., adenoviral conjunctivitis, molluscum contagiosum, herpes simplex conjunctivitis and keratitis, etc., and fungal keratitis.
Prophylactic uses of a composition of the invention also include post-traumatic prophylaxis, especially post-surgical prophylaxis, and prophylaxis prior to ocular surgery.
What constitutes a xe2x80x9cconcentration effective for treatment and/or prophylaxis of a gram-positive bacterial infectionxe2x80x9d depends, among other factors, on the particular oxazolidinone compound or compounds being administered; the residence time provided by the particular formulation of the active agent; the species, age and body weight of the subject; the particular ophthalmic condition for which treatment or prophylaxis is sought; and the severity of the condition. In the case of linezolid, an effective concentration in a composition of the invention for topical administration to an eye will generally be found in the range from about 0.1 mg/ml to about 100 mg/ml more typically about 0.5 mg/ml to about 80 mg/ml. For oxazolidinone compounds other than linezolid, an appropriate concentration range is one that is therapeutically equivalent to the linezolid concentration range indicated above.
The term xe2x80x9cophthalmically acceptablexe2x80x9d with respect to a formulation, composition or ingredient herein means having no persistent detrimental effect on the treated eye or the functioning thereof, or on the general health of the subject being treated. It will be recognized that transient effects such as minor irritation or a xe2x80x9cstingingxe2x80x9d sensation are common with topical ophthalmic administration of drugs and the existence of such transient effects is not inconsistent with the formulation, composition or ingredient in question being xe2x80x9cophthalmically acceptablexe2x80x9d as herein defined. However, preferred formulations, compositions and ingredients are those that cause no substantial detrimental effect, even of a transient nature.
Contemplated compositions are highly effective in treating gram-positive bacterial infections of the eye. Without being bound by theory, it is believed that the high concentration of oxazolidinone, facilitated by the presence of a cyclodextrin or derivative thereof, and the absence of any preservative likely to degrade or interfere with the cyclodextrin enable one to deliver a higher amount of an oxazolidinone antibiotic drug to ophthalmic tissues where it is needed most than is possible with existing formulations. Thus, one could treat or prevent bacterial infections or other conditions of an eye cited by treating the eye according to the method of the present invention.
Other advantages of the present invention will become apparent from the following description of the invention and Examples, below.